Morbidity in schistosome-infected individuals is caused mainly by the immune response of the host to schistosome eggs deposited in the tissues. In chronic schistosomiasis, fibrotic sequelae to the inflammatory reaction to the eggs are responsible for most clinical disease. Hepatic fibrosis and the granulomatous response to eggs of schistosome species pathogenic for man are studied in mice in relation to parasitologic parameters of infection. Cytokines play an important role in the genesis and regulation of the size of circumoval granulomas and in the fibrosis associated with them. Pulmonary granulomas around intravenously injected S. mansoni eggs are frequently used to study the immunopathology of schistosomiasis. This system allows better manipulation of the mouse than one obtains with infected animals. In the past year we have found major differences in immunomodulation of granulomas in this "lung model" compared to infected mice. Anti-IL-2 and anti-IL-4 antibodies and administration of exogenous IL-12 have major effects on granuloma size in the lung model but little effect on hepatic granulomas in infected mice. Granulomas around eggs injected into the liver via the portal vein behaved like those in the lung model, suggesting that the site of the granuloma was not crucial. This was confirmed by creating portacaval vascular shunts in infected mice, shunting eggs in infected animals to the lungs. Anti-IL-4 antibodies did not affect these granulomas. Granulomas injected into the lungs of infected mice were downregulated by anti-IL-4, indicating that the vigorous response of infected animals was not responsible for the failure of anti-IL-4 to modulate responses in infected mice. We believe the crucial factor to be the quality of the eggs injected in the lung model. Defining the difference between granulomas in infected mice and those in the lung model is crucial to understanding the in vivo regulation of the granulomas.